Alkoxyalkyl esters of monoiodomono-alkoxybenzoic acids



Patented Oct. 30, 1951 ALKOXYALKYL ESTERS OF MONOIODO- 'MONO ALKOXYBENZOIC ACIDS ..Sydney.Archer, Albany, NztY., assignor-to Sterling Drug Inc.,- Wilmington, Del.,- a corporation of Delaware No Drawing. Application November 24, 1947,

Serial No. 787,854

-8.Claims. 1 Thisinvention relates. to alkoxyalkyl esters of iodoalkoxybenzoic acids, whichaesters have the formula where Y is an alkylene bridge and R and R. are alkyl groups, and' wherein the total number of carbon atoms in the above formula is from 11 to 16. I prefer thecompoundswherein' Y* has 2-3 carbon atoms and R; has 1' -2 carbon atoms,

' since these are most readily available'from inexpensive starting materials.

' Although all possible combinations of the 'iodo group and the alkox group on the benzene ring form useful compounds,-certain permutations are preferred because of the relative availability of certain isomers from among the possible alkoxyiodobenzoic acids. Thexpreferred species include alkoxyalkyl esters of 3-iodo-4*-alkoxybenzoic acid,

. 2-iodo-5-alkoxybenzoic acid and 3-iodo-6-alkoxy- .benzoic acid.

. My compounds are opaque to'X-'-rays and therefore are valuable as contrast media in roentgenological examination of body cavities. They may be administered directly'into the body 'cavities to be outlined. "The are definite and stable chemical compounds in which the halogen is firmly attached to the benzene nucleus.

I have foundthat these substances are of particular value in the roentgenological examination .of the spinal cord and subarachnoid space, i. e.,

1 inthat branch of radiography known as myelography.

which is easily .andnrapidly; administered and -which distributes :itself readily. and evenly to various parts of the. cerebrospinal-system, without, however, diffusing into such thin layers that the radiopacity is lost. It shouldbe eliminated readily by adsorption from.'the spaces." rather than requiring aspiration. It-should be nonirritating to nerve tissues; and non-toxic in any other way to the patient.

Up to the present time, the various agents used for myelograph include gases such as air and oxygen," thorium: dioxide sols,-iodized oils, and, more recently, a product consisting of a mixture of ethylestersof isomeric iodophenylundecylic acids. disadvantages. Gases are poor contrast media and are difiicult to administeraproperly, since their usearequires removahof: part of ;the cerebrospinal fluid, a procedure which-may'result in dan- An ideal.;.1nyelographic. agent :is one Each of theseagents hascertain.

'the tissues.

been found to cause untoward reactions; as well 5. as introducing the-possibility of eventualinjury from residual radioactivity. .brominated oils such as iodinated poppyseedoil,

Iodinated .and

iodinated sesame oil, iodinated rapeseed oil and brominated olive oil, are effective contrast agents,

' but are not entirely satisfactory because of their high viscosity, and somewhat irritating properties.

They must be injected under pressure and. after examination be withdrawn by aspiration, for otherwise they remain largely unabsorbedfor a period of years. Oicatrix formation may result from their prolonged irritation from contact with Their high viscosity tends to cause separation of the oil into globules, rendering diagnosis diflicult. The mixture of ethyl iodophenylundecylates is undoubtedly the best myelographic agent previously produced. It is less viscous'than the iodinated glyceride oils and, therefore, is more easily introduced; withdrawn and absorbed. However; it is reported that at least a year is required for'complete absorption and elimination of as little as 0.5 to 1.0 cc. in man.

"The possibility of using water-soluble radio- .paque media as myelographic agents has been investigated, but these compounds have been found unsatisfactory for a number of reasons; Diffusion is too rapid so that the compound quickly becomesdiluted with spinal fluid, thereby losing its radiopacity unless a large possibly toxic quantity is injected. Water soluble substances also are rapidly absorbed into the circulatory system creating increased hazards of systemic poisoning.

LThe alkoxyalkyl iodoalkoxybenzoates have over the above-described For instance they are abno irritationof the spinal membranes. Experimental studies with several compounds within the scope of this invention have shown amounts required for radiologic examination are completely eliminated from the cerebrospinal system of rabbits or cats within ten to twenty-five days,

'with all butxa trace being gone in a few-days.

Similar experiments in cats and dogs with ethyl iodophenylundecylate showed appreciable amountsremaining in the spinal cord foras long as eight months. Irritation tests inrabbits eyes showed irritation of the conjunctiva by the latter compound, greater than that shown by the new compounds.

'. .Thestoxicities of thercompounds of my :invengerous complications. Thorium dioxide sols have .6512ti0m1oral1y rwintraperitioneally, are low :enough to permit the compounds to be safely used as myelographic agents. The esters of my invention have the advantage of being pure compounds instead of a mixture of isomers. They have a greater radiopacity due to a higher percentage of iodine (from 35 to 40% as compared with 30.5% for ethyl iodophenylundecylate) Certain members of these alkoxyalkyl iodoalkoxybenzoates when in the pure state may crystallize to form low melting solids. Since myelographic agents must be injected in liquid form and retained so during examination and removal, these solid esters may be rendered permanently fluid by admixture with another member of the series, forming a eutectic mixture with a melting point lower than body temperature.

My new compounds may be synthesized by the esterification of an iodoalkoxybenzoic acid by one of the following methods: (1) the iodoalkoxybenzoic acid and an alkoxyalkanol are combined directly in the presence of an acid catalyst; (2) said acid in the form of a reactive derivative, such as the acid chloride or anhydride, is caused to react with an alkoxyalkanol; or (3) a metallic salt of said acid is caused to react with an alkoxyalkyl halide.

The following examples will illustrate my invention more completely, but should not be construed as a limit to the scope of the invention, this being determined instead by the appended claims.

Example 1 Z-ethoxyethyl 3-i0do-4-methomybenzoate.-A mixture of 27.8 g. of 3-iodo-4-methoxybenzoic acid and 50 cc. of thionyl chloride is heated on a steam bath for one and one-half hours. The unreacted thionyl chloride is then removed at reduced pressure and 50 cc. of 2-ethoxyethanol is added followed by additional heating for a half hour. The mixture is poured into ice-water and the product extracted with ether. The ether extracts are Washed with water, dilute sodium car- 7 bonate solution and again with Water, and dried over anhydrous sodium sulfate. After removal of the ether the product distils at 163-173 C. (0.8-1.3 mm.); yield about 28 g. Redistillation gives a purer sample of 2-ethoxyethyl 3-iodolmethoxybenzoate, B. P. 163-165 C. (0.06 mm.), M. P. 50.5-52.5 C.

Example 2 yield about 23 g., M. P. (SB-64 C. i

Example 3 Example 4 3-ethoxypropyl 3-iodo-4-ethoxybenzoate is pre- .pared in the manner described in Example 2 using .:;as starting materials 3-iodo-4-ethoxybenzoic.acid:

and 3-ethoxypropanol. It distils at 84- 85 d. (0.8 mm.)

Example 5 Z-butoxyethyl 3-iodo-4-methoxybenzoate is prepared in the manner described in Example 2 using as starting materials 3-iodo-4-methoxybenzoic acid and 2-butoxyethanol. It distils at 192- 194 C. (0.8 mm.)

Example 6 3-methoxypropyl 3-iodo-4-methoxybenzoate is prepared in the manner described in Example 2 using as starting materials 3-iodo-4-methoxybenzoic acid and 3-methoxypropanol. It distils at I'll-172 C. (0.8 mm.)

Example? 2-ethoxyethyl 2-iodo-5-methoxybenzoate is prepared in the manner described in Example 2, using as starting materials 2-iodo-5-methoxybenzoic acid and 2-ethoxyethano1. It distils at 173- l'75 C. (0.6 mm.).

I claim: 1. A compound having the formula COO,YOR1 I where Y is an alkylene bridge of 2 to 3 carbon atoms and at least two carbon atoms separate the carboxyl group from the OR group, and R and R are alkyl groups of such a size that the total number of carbon atoms in the molecule does not exceed 16.

3. A compound having the formula where Y is an alkylene bridge of 2 to 3 carbon atoms and at least two carbon atoms separate the carboxyl group from the OR, group, and R is an alkyl group of 1-5 carbon atoms.

4. 2 butoxyethyl 3 iodo 4 methoxy benzoate, having the formula CH30 COOCHzCHzOCHzCHzCHzCH! 5. 3-methoxypropyl 3-iodo-4-methoxybenzoate,

having the formula GHSO oooomoflzonzoonl 6. 2 ethoxyethyl 2-iodo-5-methoxybenzoate, having the formula oooomomoomom CHBO COOCHzGHaOCHzCH;

8. 3 ethoxypropyl 3-iodo-4-eth0xybenzoate, having the formula C O O CHlCHZCHZO CHzCH;

SYDNEY ARCHER.

CIHaO REFERENCES CITED 15 The following references are of record in the file of this patent:

Number Number 6 UNITED STATES PATENTS Name Date Grether et a1 Oct. 17, 1939 Grether et a1 Apr. 23, 1940 Grether et a1 Apr. 23, 1940 Grether et a1 Mar. 11, 1941 Tallman et a1. May 7, 1946 FOREIGN PATENTS Country Date Great Britain July 25, 1939 Great Britain Jan. 30, 1940 OTHER REFERENCES ODonnell et a1.: J. A. C. 8., vol. 68, p. 1865 Certificate of Correction Patent No. 2,572,828 October 30, 1951 SYDNEY ARCHER It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 2, line 55, for intraperitioneally read intmpen'toneally; column 3, line 69, for zoic and read zoic acid and;

and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 5th day of February, A. R 1952.

THOMAS F. MURPHY,

Assistant Omission of Patents. 

1. A COMPOUND HAVING THE FORMULA 